Apparatus, methods and kits for simultaneous delivery of a substance to multiple breat milk ducts

ABSTRACT

Apparatus, methods and kits for simultaneous delivery of a fluid or other substance to two or more breast milk ducts are provided. The fluid can be delivered for a variety of purposes including lavage of the ducts and administering an agent for therapeutic, prophylactic, or diagnostic purposes.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 09/506.477 filed Feb.29, 2000. This application claims the benefit of each of the followingprovisional applications under 37 CFR §1.78: 60/122.076, filed Mar. 1,1999; 60/134.613. filed on May 18. 1999; 60/143,476, filed on Jul. 12.1999; 60/143,359, filed on Jul. 12. 1999; and 60/170.997, filed on Dec.14, 1999. The application is also related to non-provisional application09/473.51-9, filed on Dec. 28, 1999. The full disclosures of eachapplication are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to medical devices and methods.More particularly, it relates to devices and methods for the delivery ofsubstances to breast milk ducts.

2. Background of the Invention

The current state of the ductal access art is that the ducts in a breastare accessed one-by-one with a catheter. The human breast has from 6-12ducts. This process of duct-by-duct access has many disadvantages,including that the process is slow and that it is very difficult afterfinishing lavage of one duct to know which of the other ducts of abreast have or have not been lavaged. Thus, under the one-duct-at-a-timeduct lavaging or accessing system it is easy to miss a duct or access orduct twice. The present invention at least partly overcomes thesedeficiencies.

U.S. Pat. No. 5,763,415 to Sukumar claims a method of treating theductal epithelium of a mammary glad prophylactically for cancer byductal cannulation and administration of a vector comprising thymidinekinase into the duct. The delivery of epithelium-destroying agents tobreasts by ductal cannulation is described in WO 97/05898.

Various methods and techniques of duct-by-duct access have beendescribed, including methods described in Love and Barsky, (1966) Lancet348: 997-999, and Presentations about ductal access made in Love, (1992)“Breast duct endoscopy: a pilot study of potential technique forevaluating intraductal disease,” presented at 15th Annual San AntonioBreast Cancer Symposium, San Antonio, Tex., Abstract 197; Barsky andLove (1996) “Pathological analysis of breast duct endoscopedmastectomies,” Laboratory Investigation, Modern Pathology, Abstract 67;and Lewis (1997) Biophotonics International, pages 27-28, May/June 1997.

A company called Diagnostics. Inc. formed in 1968, produced devices toobtain breast ductal fluid for cytological evaluation. The devicesincluded a breast duct catheter to infuse fluid into and collect fluidfrom individual ducts. The devices were sold prior to May 28, 1976 forthe purpose of collecting breast ductal fluid for cytologicalevaluation.

A patent application entitled “Methods and kits for obtaining fluid andcellular material from breast ducts,” U.S. Ser. No. 09/067,661 filedApr. 28, 1998, and its continuation-in-part, U.S. Ser. No. 09/301,058filed Apr. 28, 1999, describe and claim infusing a small amount of fluidinto the duct and collecting the fluid using a catheter. Relatedapplications include U.S. Ser. Nos. 60/143,476 and 60/143,359, bothfiled Jul. 12, 1999, 60/134,613, filed May 18, 1999, and-60/114,048filed Dec. 28. 1998, all of which are herein incorporated by referencein their entirety. Provisional application No. 60/170,997, filed Dec.14, 1999, and non-provisional application 09/473,510, filed Dec. 28,1999 describe methods and apparatus for delivering a substance to abreast duct.

SUMMARY OF THE INVENTION

Apparatus for accessing two or more ductal networks in a breast comprisetwo or more individual access probes, each probe having a lumen andbeing configured for insertion through an orifice of a ductal network.The apparatus further comprises a manifold having an inlet for receivinga fluid and two or more outlets, one each for distributing and/orcollecting the fluid to each of the probe lumens. The manifoldpreferably connects to more than two probes, usually to at least threeprobes, more usually to at least six probes, and even more usually to atleast twelve probes. Optionally, the probes may be selectively andremovably connected to the manifold in any number up to the totalnumber. In one embodiment, the total number of probes are pre-connectedto the manifold and at least some of the probes have valves or othermeans for selectively closing the probe lumen. The apparatus can furthercomprise a pump that connects to the manifold to deliver and/or aspiratea fluid to the manifold. The pump can comprise a syringe that ispre-loaded with a wash or other fluid. Each probe lumen is optionallyconnectable to a collection lumen to collect a sample from each ductseparately.

The apparatus can further comprise a plurality of fluid collectiontubes, and the tubes are connected or connectable to the probe lumen.Thus is provided an apparatus for accessing a plurality of ductalnetworks in a breast, comprising a plurality of individual accessprobes, each probe having a lumen and being configured for insertionthrough an orifice of a ductal network; and a manifold having an inletfor receiving a fluid and a plurality of outlets for distributing thefluid to each of the probe lumens.

A method for delivering a substance to two or more ductal networks in abreast is provided comprising establishing access to two or more ductalnetwork in the breast through a ductal orifice of each ductal network;and thereafter delivering a substance to and/or collecting a fluid fromtwo or more of the ductal networks. Establishing access comprisesinserting an access probe in each ductal orifice to be accessed. Atleast some of the access probes are fluidly connected by a manifold sothat substance may be delivered simultaneously to the connected probesthrough the manifold. All of the access probes are fluidly connected tothe manifold so that fluid may be delivered simultaneously to allprobes. The substance is delivered simultaneously to all of the accessedductal networks. Fluid can be collected in separate receptacles for eachductal network. The access can be established to each of the ductalnetworks in a breast.

A method for delivering a fluid to two or more ductal networks in abreast is provided comprising locating two or more ductal networks in anipple of the breast, inserting an access probe through an orifice ofeach of the located ductal networks; and infusing the fluid through amanifold to each of the probes. The method further comprises connectingindividual probes to the manifold so that the number of probes connectedto the manifold is the same as the number of probes inserted into ductalorifices.

The method further comprises providing an assembly comprising a numberof access probes greater than the number of ductal orifices. The accessprobes can be pre-loaded on the manifold, while selectively blockingthose access probes connected to the manifold which are not inserted toa ductal network. The method can further comprise collecting fluid fromeach accessed ductal network, wherein the fluid is collected separatelyso that no one fluid from a ductal network is mixed with fluid fromanother ductal network.

A kit for delivering a substance to a two or more of ductal networks ina breast, is provided comprising two or more of probes each having alumen and being configured for introduction into a ductal network of thebreast, and instructions for use setting forth a method according to anyof claims identified herein. A kit is also provided comprising amanifold having an inlet and at least twelve outlets, and at leasttwelve access probes connectable to the outlets on the manifold. Theaccess probes are configured for insertion through an orifice of aductal network of a breast. The kit can further comprise a separatecollection receptacle for each probe.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a basic multiple duct infusion apparatus.

FIG. 2 shows a basic multiple duct infusion and collection apparatus.

FIGS. 2A, 2B, 2C1 and 2C2, are detailed cross-sectional views of theapparatus of FIG. 2.

FIG. 3 shows a basic multiple duct infusion and collection apparatusaccessing multiple breast ducts of a breast.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

The following preferred embodiments and examples are offered by way ofillustration and not by way of limitation.

Apparatus according to the present invention for accessing two or moreductal networks in a human breast comprises a manifold having two ormore outflow ports connected or connectable to probes, catheters orother like members having lumens, each capable of accessing a breastduct and configured to infuse and optionally collect fluid or otherinfusible material into accessed breast ducts in a human breast. Themanifold has an inlet for receiving fluid from a connectable fluidsource, such as a pump or syringe, and a plurality (e.g. two or more)outlets for distributing the fluid to a lumen in each of the probes.Usually, the manifold will have a total of at least three, more usuallyat least six and preferably at least 12 outlets, thus providing capacityto connect 12 or more probes in order to access and infuse all of theaverage 9-12 ducts in a human breast. Optionally, the probes may beremovably attached to the manifold outlets. Thus, depending on thenumber of ducts to be accessed in a procedure, the same number of probelumens can be attached at outlets on the manifold. The inlet on themanifold receives fluid from a fluid source, e.g. a syringe, pump, orother fluid delivery unit capable of providing a fluid inflow under acontrolled pressure to the manifold. The syringe, pump, or other fluiddelivery unit can be pre-loaded with a fluid (in pre-measured volumes)or other material to be delivered to two or more ducts through themanifold. The fluid can comprise a substance and/or an agent tofacilitate collecting ductal contents (e.g. to collect cells or otherdebris from the duct), or the fluid can comprise a substance and/or anagent that comprises e.g. a therapeutic agent, a prophylactic agent, ora diagnostic agent.

The outlets may additionally have valves or other elements to controlfluid flow into the outlets and/or inhibit backflow of fluid from theduct, e.g. a stopcock or other such element. The fluid controllingelements can be at the manifold outlets or on the probe itself. Thus, atleast some of the probes (e.g. two or more) can be pre-connected to themanifold and have means for selectively closing (or opening) the probelumens, e.g. for receiving an infusion fluid from the manifold, orstopping any back flow from entering the manifold from the duct so thatsuch material can be diverted to a separate collection receptacle, asdescribed below. Such a control element is useful, e.g. where a duct hasbeen filled and it is desired that any collectable fluid be isolatedfrom other collectable fluids from the other ducts. The probe lumensmight also be selectively closed after the ducts have been filled duringa massaging of the breast, in order to retain fluid in the ducts and notallow it to flow back into the infusion lumens of the probes i.e. tokeep it from leaving through the outlet in the manifold.

The probes will have an infusion lumen, e.g. which is directly connectedto the manifold unit, and will preferably also have a collection lumene.g. that branches from the infusion lumen for separately collectingfluid from each duct. Each probe will preferably have a separatecollection tube having a lumen in order to collect a sample from eachduct separately. Thus, the apparatus can comprise a plurality of fluidcollection tubes, and the tubes will each be individually connected orconnectable to individual probes. A fluid control valve can close theinfusion lumen to inhibit backflow of collected fluid to the manifold,and/or to divert the collected fluid to the fluid collectionreceptacles. Thus the apparatus can be used for accessing a plurality ofductal networks in a breast with a plurality of individual accessprobes, each probe having a lumen and being configured for insertionthrough an orifice of a ductal network. A manifold having an inlet forreceiving a fluid and a plurality of outlets distributes the fluid toeach of the probe lumens, and optionally the fluid may then be collectedthrough collection tubes which branch from the infusion lumens in theprobes so that isolation of the collected fluids can be maintained.

Turning now to the figures, FIG. 1 illustrates an apparatus 10 having amanifold structure 18 which branches into two probes 12 and 22. Amanifold inlet 20 receives a fluid from a fluid source, such as syringe24. Probe 12 has a stop 16 to prevent excessive penetration into theduct by tip 14. The stop can be a disk, flange, or other protrusion onthe probe to prevent the probe from penetrating the duct passed acertain point. Useful dimensions for the probe and probe tip aredescribed, for example, in copending application Ser. No. 09/473,510,the full disclosure of which has previously been incorporated byreference. Probes 12 and 22 have infusion lumens which are infused withfluid through manifold 18 and inlet 20 from fluid source 24. Inaddition, the probes that access the ductal networks can have some formof attachment member to attach the probe or lumen to the duct to keep itfrom falling out of the duct once the duct is accessed. This could be anenlarged segment, e.g. a sphere or oval, that passes just inside thesinal sphincter and holds the lumen in place, or a wire or tether fromthe lumen to the breast skin to be held with an adhesive or othertemporary anchor. Other systems can be designed into the probe unitsthat provide the same tethering or anchoring effect.

FIG. 2 illustrates a multiple duct infusion and collection apparatus 28having a syringe 40 or other fluid infusion unit for placing fluid in aninlet 42 of a manifold 30. The syringe 40 or other fluid infusion unitcan be preloaded with wash fluid or other agent for delivery to two ormore ducts. Individual probes 44 are removably attachable to outlets 45formed on the manifold 30. As described previously, this allows the userto connect a number of probes 44 equal to the number of ductal orificesto be accessed in the procedure. Those outlets 45 which are not used canbe blocked, for example, by using a cover 47 which is placed over theoutlet. Alternatively, valves could be provided in the manifold, or eachof the outlets 45 could be covered by a breakable seal which is onlyopened if that outlet is to be connected to a probe 44.

Referring to FIG. 2B, each probe 44 may be provided with a manuallycontrollable valve 38 or other fluid control element, such as a one-wayvalve. The valve 38 will allow the user to selectively isolateindividual probes 44 at a point between the syringe 40 and the breast.Such isolation is useful in at least two circumstances. First, if one ormore probes 44 are not to be used, they may be simply turned off. Thus,to an extent, valve 38 is an alternative to valves or other sealingmeans which may be provided on the manifold 30. Additionally, the valve38 may be used when it is desired to remove an infused fluid from theductal network of the breast. In that case, the valves 38 would beclosed, and fluid aspirated or otherwise collected through a collectiontube 36 which is attached to a lumen of the probe 44 upstream of thevalve, i.e. at a point between the valve and probe tip 32 which isintroduced into the orifice of the ductal network. Optionally, thecollection tube 36 may also include a valve 37 for isolating thecollection tube from the lumen of probe 44. Usually, probe 44 will alsoinclude a stop plate or flange 34, as generally described in connectionwith FIG. 1.

The probes of the present invention will include at least a singlelumen, where the lumen is used at least for introducing fluids into aplurality of ductal networks in a human breast, as described previously.Usually, the lumen(s) will also be used for aspirating and collectingfluids from the ductal networks. In the latter case, the lumen may be asingle lumen 49, as illustrated in FIG. 2C 1. Alternatively, the lumencould be divided into an infusion lumen 51 and aspiration lumen 53 asillustrated in FIG. 2C 2. The use of a single and dual lumen devices isdescribed in copending application Ser. No. 09/473,510, which haspreviously been incorporated herein by reference.

Referring now to FIG. 3, use of the ductal infusion and collectionapparatus 28, described above, for delivering and collecting a wash ortherapeutic fluid to a human breast B will be described. Tips 32 ofprobes 44 will be introduced through orifices of the individual ductalnetworks in the breast, as generally described in the prior copendingapplications which have been incorporated herein by reference. Althoughonly two probes 44 are shown introduced to the breast B, it will beappreciated that a larger number of probes, usually up to the totalnumber of orifices in any breasts (e.g. 12) may be simultaneously and/orsequentially introduced to the breast. Once the tips 32 of the probes 44are introduced, they may be optionally anchored in place, e.g. usingtethers 68 which are attached to adhesive pads or other anchors. Fluidmay then be introduced into the multiple ductal networks simultaneouslyusing a single syringe 40 or other fluid infusion unit, e.g. a pump. Thefluid will be introduced in a volume and at a pressure selecteddepending on the purpose of the procedure. After the fluid has beenintroduced, the valves 38 may be closed in order to hold the fluid inthe ductal networks and prevent backflow of the fluid from the networksinto the manifold 30. Optionally, the breast B may be massaged at thispoint in order to distribute the fluid within the ductal networks. Whenit is desired to remove the fluid, individual valves 37 in thecollection tubes 36 may be opened in order to permit flow from theductal network to a collection device, such as syringe 60. The use of asyringe or other collection device having an aspiration capability ispreferred, but not necessary since at least a portion of the fluid couldbe removed by simply allowing it to flow out and/or pressuring thebreast to force the fluid out.

The subject apparatus have an inlet which can be made e.g. of a plasticor other material, e.g. preferably a disposable material that can besterilized. The inlet can be rigid or flexible so long as it canaccommodate an instrument that delivers the substance through the inlet.For example, the inlet can be cylindrical for receiving a syringe tip.In that case, the instrument to deliver the substance into the inlet canbe, e.g. a syringe capable of being loaded with the substance and havinga tip capable of accessing the inlet. The syringe can be a syringeadapted for use in this apparatus (e.g. without a hypodermic needleattached to the tip) as described in U.S. Pat. Nos. 5,308,331,4,391,272, 4,775,364, 4,863,427, 4,929,231, 4,932,941, and U.S. Pat. No.4,950,243, which describe disposable single-use syringes. The syringe ordelivery instrument may also be reusable. The syringe may be adaptedfrom the pre-filled syringe described in U.S. Pat. No. 4,878,903. Theadaptations can comprise that the syringe accesses the inlet havingaccess to two or more outlets and/or probe lumens that are capable ofaccessing a breast duct. The access and connection between theinstrument to deliver the substance and the inlet can comprise a nestedfit configuration of a syringe tip into the inlet, or a connectioncomprising threads on the inside or outside of the inlet and/or on theinside or outside of the syringe tip so that the syringe tip and theinlet can be attached to each other by screwing one into the other.Other connections such as a snap connection, for example, or any otherway to fit a delivery instrument into an inlet can be used.

Instruments other than a syringe can be used to deliver the substanceinto the inlet, particularly depending on the volume of substance to bedelivered, and the consistency of the substance. For example, aninstrument having a piston or other method of pushing a substance intothe inlet can be used. A volume of liquid can be delivered, for examplefrom a bag having a tube connectable or accessible to the inlet, anddelivery of the substance can occur by placing the bag above the inletand opening the tube access so that the liquid can flow into the inletby gravity. The flow of the substance into the inlet in this case can becontrolled by a stopcock or other such on/off regulating mechanism,including the potential to lower and raise the rate of flow to achieve aslow, intermediate, or high rate of delivery. The advantage of a syringeused as the delivery instrument is that it can provide a necessarypressure on the substance as it passes into the inlet for delivery tothe ducts, and that applied pressure can be calibrated and controlled bypushing the syringe plunger at a certain rate or with a certain force.

Whatever the delivery instrument that is used, preferably the deliveryinstrument is calibrated and the pressure that can be applied from theinstrument is quantifiable and preferably also the pressure iscontrollable so that a faster or slower rate of flow can be generated asneeded for the particular delivery purpose. For example, as describedbelow the lavage embodiment of the delivery apparatus requires that theflow be controllable from at least the inlet of the apparatus, andpossibly also from outflow lumens as well.

The inlet is connected to two or more inflow lumen or probe lumens.Thus, in a simple embodiment, an inlet is connected to two inflow lumensand the substance passes through the inlet into each of the two inflowlumens. A typical human breast has from 6 to 12 milk ducts on average,and thus 6 to 12 ductal orifices. In a procedure involving diagnosticanalysis of the breast by analyzing the breast duct fluid and cells itis desirable to access all of the breast ducts in the breast. Thisaccess can be accomplished at the same time or virtually simultaneouslyusing the apparatus of the invention (i.e. using the same procedure asopposed to multiple procedures).

In addition, the apparatus provides an opportunity to minimize thetissue stress to the patient where the steps of massaging and squeezingare applied to the breast, e.g. in a lavage procedure. Using theapparatus allows approximate simultaneous access and approximatesimultaneous delivery of the lavage agent to the accessed ducts;thereafter and during the infusion of lavage fluid the practitioner canmassage and/or squeeze the breast, affecting the fluid and cell yield ofall the accessed ducts in the same massaging and/or squeezing action,and thereby cutting down the amount of massaging and/or squeezing of thebreast required for the entire procedure. Massaging and/or squeezing ofa breast having ducts accessed in a duct-by-duct fashion, requiresmultiple massaging and/or squeezing applications to the breast, andrisks the inevitable increased discomfort to the patient and potentialdamage to the breast tissue by repeated handling.

In order to construct a generic apparatus capable of use by allpatients, a inlet is connected to a plurality of outlets which can eachconnect to an inflow lumen or probe lumen. The amount of inflow lumensrequired should be at least more than 3, or around 6 or more, ortypically about 12. Thus the apparatus can comprise about 6 to about 12or more outlets and a one-to-one option of corresponding connectableinflow lumens (and also, perhaps, having additional inflow lumens, oroptions to add additional inflow lumens) so that the total potentiallyusable lumens or outlets in the apparatus are in a range of from about12 to about 16 in order to cover the rare individual who has more milkducts than the norm. However, not all outlets need to communicate with abreast duct (in any given procedure), and those outlets and/or inflowlumens not in use can be capped or blocked. Thus an embodiment of theapparatus is an inlet connected to exactly the number of operableoutlets and inflow lumens as the patient has breast ducts, and which itis desirable to access, while unused outlets remain capped or blockedfrom delivering the substance or connecting to a probe or inflow lumen,although possibly still capable of communication with the inlet. Anotherembodiment of the apparatus is an inlet connected to exactly the numberof outlets and/or inflow lumens as the patient has breast ducts thatrequire therapeutic treatment or access for other purpose, while theunused outlets remain capped or blocked from delivering the therapeuticsubstance. For example, a patient having 3 affected ducts will have theinlet operably connected to 3 outlets and 3 inflow or probe lumens, andeach of those inflow lumens will access an affected duct.

The connection between the inlet and the outlets can be removable. Theremovable connections can include a member to control a flow of thesubstance, for example a stopcock or valve. The removable connectionscan also include a cap to block connection with an inflow lumen. Thislatter embodiment is useful when the apparatus or manifold has moreconnections to inflow lumens than the patient has ducts on her breast,e.g. where the manifold has 12 connections and the patient has 10 ducts,two outlet connections may be capped to prevent passage of thesubstance. The other 10 connections can be connected to inflow lumensthat access each of the 10 ducts.

The connection between the inlet and the inflow lumens and/or theoutlets can be of molded plastic or other polymers, including e.g.resilient, rigid or flexible materials. Multiple lumens together mayform a manifold having a inlet and multiple branching lumens. Betweenthe inlet and the inflow lumens can be a volume of a very small capacityor a volume of larger capacity for holding the substance as it isdispersed to the various inflow lumens. Thus the volume between theinlet and the inflow lumens can be e.g. a cylinder, a disk, a bulb, oran amorphous shape that expands with the introduction of fluid. Therequirements of this intermediate volume and its shape may be dictatedby such parameters e.g. as the desired pressure of delivery of thesubstance, and the viscosity of the substance, and other parameters aswell including, e.g. optimal shapes for handling, use, and attachment ofinflow lumens. For example the needs for the volume in a lavageprocedure may vary from those of simple delivery of an agent to theducts.

The distal end of each inflow lumen operably connected to the inlet andmanifold at the outlets accesses a breast milk duct through a ductalorifice. Thus, e.g. where two ducts are accessed, two inflow lumens areconnected to the inlet each at an outlet; where all the ducts on a givennipple are accessed, e.g. where the particular breast being accessed has8 ducts, then 8 inflow lumens are operably connected to the inlet fordelivery of a substance to the 8 accessed ducts.

The inflow or probe lumens can be any lumen capable of transferring asubstance to the breast duct. Thus, for example, catheters and cannulasmay be inflow or probe lumens. The lumen may have multiple segments,e.g. a flexible lumen for extending flexibly to its correspondingoutlet, and a rigid lumen at the distal end where ductal access occurs,the rigidity facilitating in part the access to the duct through theorifice. The multiple segments, e.g. the flexible and rigid portions maybe permanently connected or removable. Catheters for delivery or lavagecan have features essentially as available e.g. as described in thefollowing patents: U.S. Pat. Nos. 5,279,551, 4,957,484, 5,827,237,5,810,867, 5,810,789, 5,807,329, 5,797,869, 5,795,326, 4,795,424,5,702,365, 5,683,640, 5,649,909, 5,637,102, 5,599,324, 5,364,344,5,350,358, 5,333,609, 4,682,978, and U.S. Pat. No. 5,207,648. Alsopatent application Ser. No. 09/473,510, filed Dec. 28, 1999 (copendingand co-owned with the present application) describes useful catheterfeatures and elements that can be incorporated into the presentapparatus to useful effect.

A duct probe inserted into the ducts to dilate the ducts can accomplishaccess of the ducts. In the past, ductal access has generally beenaccomplished by placing galactography needles or dilators of increasingsizes into the ductal orifice to dilate the orifice to a diametersufficient to accept the subject lumen. The state of the art has been toplace a small galactography needle or dilator into the duct, remove it,replace it with an incrementally larger needle or dilator, remove that,and replace it with a still larger needle or dilator, and so on.Eventually the needle or dilator occupying the orifice is the same sizeor just larger than the subject lumen. That needle is removed andreplaced by the lumen of a catheter or cannula or other like tube andthe procedure can continue from there.

Instead of using multiple needles or dilators of ascending size, a ductprobe that is a separate single graduated unit can be used. The ductprobe can be replaced by the inflow lumen once the duct is sufficientlydilated, or the duct probe can be a unit that is connected to the inflowlumen. Where the unit is connected to the inflow lumen, the duct probecan be a cannula-like member essentially constructed as described inU.S. Pat. No. 5,593,393, with adaptations and adjustments to probe anddilate a breast duct rather than a lacrimal duct, and the cannula can beconnectable to an inflow lumen that is connected to the inlet. Thus, theapparatus may comprise inflow lumens capable of accessing, dilating anddelivering a substance to the breast duct with a single entry.Alternatively, the pre-dilation may be accomplished with a separatetool, e.g. successively larger galactography needles or a singlegraduated duct probe, or may be accomplished by a tool integral to theinflow lumen, having itself a lumen for delivering the substance. Wherethe lumen then accesses the duct, the tip of the lumen is designed forsuch access, e.g. as described in U.S. Pat. No. 4,543,087. The accessmember or duct probe, whether separate from or attached to the inflowlumen, can be modified from basic needle designs available fromcompanies that provide such medical tools, e.g. Ranfac Corporationlocated in Massachusetts (phone 888-821-0098), Medical DeviceTechnologies, Inc. located in Gainesville, Fla. (phone 352-338-0440),and Cook, located in Bloomington, Ind. (phone 800-545-0890). In anyevent, whether the duct probe is connected to the catheter lumen orwhether the duct probe is removable or separate from that lumen, itsdimensions can be dictated primarily by the goals of dilation of theorifice, namely that the tip must be able to access an undilated ductalorifice, and its graduated portions must be expanded or expansive to apoint that dilates the duct to a point that provides either comfortabledelivery from an inflow lumen attached to the probe or comfortable andeasy access by the inflow lumen (as the probe is replaced). For adiscussion generally of some of the differences in catheter design andhow the design can affect resulting function see Walters et al, (1997)Int J. Artif Organs 20(4):208-12.

The probe or lumen can be made of a rigid material and can be graduated,being narrow at a distal end that accesses the duct first, and expandedat a proximal end capable of contacting a catheter or extending outsidethe duct. The fact that the probe is graduated provides a means todilate the opening at the ductal orifice for allowing access of acatheter or other inflow lumen for delivery of a substance. The probecan be a solid member, or the probe can be a tube having a hollowportion allowing fluid flow. The probe can have more than one lumen,e.g. a dual lumen probe.

The probe can further comprise a means for anchoring the member so thatthe access member does not slide out of the duct. The attachment meanscan comprise any system that anchors or fixes the access member into theduct during the delivery or lavage procedure. Thus, fasteners can beconstructed that are integral (e.g. welded or molded to) the probe oraccess member. The fastener can be anything that allows attachment of atether to the probe, e.g. the fastener can be a hook, an eye, a regionof ridges on the probe, or other means capable holding a tether at afixed point or region on the access member. A tether is then attached tothe fastener for tethering the member accessing a duct to the breast andessentially also to the duct. When the probe is accessing the duct, thefastener will be optimally located about even with or just above thenipple surface. The tether that attaches to the fastener portion of theprobe can be anything that can attach at that point and be comfortablyand securely affixed to the skin of the breast for anchoring the probein the duct. Thus, the tether can be a string, line, wire or tape, forexample. The tether is affixed to the skin of the breast by a suitable,removable means, e.g. a tape that can adhere to skin. Attachment meanson the probe can include e.g. a hook or an eye (the hook or eye beingtethered to the breast or other anchor). The probe may also be designedto have modalities that cause the access member to stay in the ductwithout tethering the member to the breast. Thus, e.g. the probe oraccess member can have ridges located below the ductal orifice, smallnon-puncturing barbs located below the ductal orifice, or perhaps awidened region of the accessing lumen located below the ductal orifice,optionally with some striations or a rough region that can grab theductal lumen near the orifice and retain the access lumen in the ductduring the delivery procedure. A knob can be placed on the probe thatpasses through the lactal sphincter and hugs the lumen once at thatposition. The ridges, rounded barbs, of striated and/or widened regionmay serve to keep the lumen inside the duct without the need to actuallytether the access tool to the breast. Ridges can be placed on the lumenat the region below the orifice, or above the orifice for attaching atether. Where a line or other tether is tied to the fastener, thefastener can be located e.g. about 2-3 centimeters from the distal tip,or in the range of from about 1 centimeter to about 8 centimeters fromthe distal tip. When the probe has accessed the duct, the fastenerholding the tether is approximately flush with the nipple surface and atthe ductal orifice. In the tether embodiment, the tether can be affixedto the skin (of the breast) e.g. by tape or other adhesive to anchoreach probe to the accessed duct and prevent the probe or any attachedcatheter from sliding out of the duct during a procedure.

The means for anchoring the probes or access members that access themilk ducts can also comprise a plate having holes for containing theaccess lumens and a slidable ring or seal at each hole that allow theplate to be pushed to the nipple surface once all the target ducts havebeen accessed, thus holding the lumens in place because the lumens areanchored into the plate (e.g. by the ring or seal), and the plate onceplaced at the nipple surface remains there. Optionally, the plate can beanchored to the nipple surface, e.g. by a few tethers located on theplate and the tether can then be affixed by some adhesive means (e.g.tape) elsewhere to the skin of the breast. The plate can have multipleholes so that the plate can accommodate a various number of accesslumens at various locations on a given nipple surface. Thus the plate istypically constructed to meet the generic needs of any patient having alavage procedure by a apparatus capable of accessing of more than onemilk duct at the same time, taking into account that the number of ductsaccessed and their locations vary from patient to patient and withvarious contexts for the lavage or delivery procedure.

The apparatus for delivering a substance to the breast ducts can furthercomprise a separate collection lumen branching from the probe lumen forcollecting the fluid delivered to the ducts, mixed with other ductalcontents including fluid, cells and other elements in a breast duct,e.g. for use in a lavage procedure. The collection is positioned so asto divert fluid back flow from the duct to the collection receptacle andprevent flow back into the main chamber of the manifold. A control valvecan be placed in the probe lumen above the collection lumen to controlback fluid flow. The collection lumen can further comprise a collectionreceptacle at its distal end for collecting the fluid that comes fromthe duct diverted through to the collection lumen. For example in thecase of a lavage procedure, the inflow or infusion lumen will deliverthe lavage or wash fluid into a duct, and the collection lumen willretrieve some of this fluid mixed with ductal fluid that can becollected in the collection receptacle at the distal end of thecollection lumen. Each duct can have a separate collection receptacle atthe distal end of its collection lumen. These receptacles can be labeledto correspond to the duct. Such a collection procedure provides thepractitioner with fluid and cell samples from each accessed duct so thatanalysis can be made of each duct separately, and a disease conditionwhen detected is localized to a specific duct. Multiple fractions may becollected from a given outflow lumen into separate collection tubes.

In the case of using the apparatus for a lavage procedure of the ductsof a breast, other features can be added to the apparatus. For example,each collection lumen can be connected to a syringe or other receptacleor mechanism capable of providing a vacuum and/or also receiving thefluid and cells. Thus, when a syringe delivers a lavage fluid throughthe inlet to the inflow lumens and to the ducts, the collection syringesconnected to distal ends of the collection lumens can be pulled back toincrease the yield of wash fluid containing ductal fluid and cells bycreating a vacuum pressure. During this modified lavage procedure usingvacuum pressure at the collection lumens, the inflow pressure and theoutflow pressures can be adjusted and adjustable to fit the particularneeds of the procedure while it is on going. For example, the inflowrate can be increased in the beginning of the procedure to ensure thatas much fluid is delivered to the accessed ducts as possible. Also beexample, once the ducts have been filled, the outflow negative pressuremay be applied to the outflow lumens to encourage the fluid filling theducts to leave the ducts through the outflow lumens.

The fluid infusion syringe and the collection syringes (or otherdelivery and/or suction mechanisms) can be connected so that thesereciprocal pressures can communicate, e.g. where the inflow pressureincreases, the various outflow pressures of the various accessed ductswill also increase. Generally the pressures of the collection syringesneed to be monitored so that they do not exceed a limit that would causean accessed duct to collapse, which limit is dependent on suchparameters as e.g. the amount of fluid in the duct or ducts, the numberof accessed ducts and the fluid inflow rate from inlet and in the inflowor probe lumens.

Substances that can be delivered to the breast milk ducts include anysubstance a practitioner might desire to deliver to a breast duct. Suchsubstances can include, e.g. a lavage fluid for washing the ducts, adiagnostic agent, a prophylactic agent, a therapeutic agent, or an agentto occupy space in a duct.

The lavage fluid can be delivered to the ducts for the purpose ofcollecting ductal fluid mixed with lavage fluid. The retrieved mixtureof wash and ductal fluid may also contains ductal epithelial cells andother ductal and cellular components (e.g. including molecular species)that can provide the basis of an analysis of the condition of the breastmilk ducts. Lavage fluid can be a saline solution, e.g. normal saline,or phosphate buffered saline (PBS), or other fluid capable and suitablefor washing a body duct. The lavage fluid will generally bebiocompatible and nontoxic to the patient. The lavage fluid can furthercomprise additives to facilitate the lavage of the duct, e.g. agentsdisclosed in U.S. Ser. No. 60/114,048 filed Dec. 28, 1998, which areincorporated by reference in their entirety.

The substance delivered to the accessed breast ducts can be a diagnosticagent. Such an agent can diagnose a condition including a cancer orprecancer condition, including atypical ductal hyperplasia (ADH) and lowgrade ductal carcinoma in situ (LG-DCIS). The agent may also have theability to diagnose other breast related conditions, including, e.g.fibrotic, cyst or conditions relating to lactation. Diagnostic agentscan include targeting diagnostic and therapeutic agents disclosed inU.S. Ser. No. 60/102,829 filed Oct. 2, 1998 and U.S. Ser. No.09/410,336, filed Oct. 1, 1999 herein incorporated by reference in theirentirety.

See co-owned and co-pending U.S. Ser. No. 09/473,510, filed Dec. 28,1999 and PCT application no. 99/31086, filed Dec. 27, 1999 both fordescriptions of other agents (diagnostic, therapeutic and/orprophylactic) deliverable to the ducts using the apparatus, methods andkits. The substance delivered to the ducts can be a prophylactic ortherapeutic agent including, e.g. a cytotoxic, cytostatic, apoptotic ordifferentiating agent. Some such agents are listed in U.S. Pat. No.5,763,415 and WO 97/05898 both to Sukumar. Other agents include, e.g.estrogen activity modulators as described in co-owned and co-pendingapplication U.S. Ser. No. 09/313,463 filed May 17, 1999, hereinincorporated by reference in its entirety.

A substance delivered to the duct to occupy space in the duct can be agel or liquid that can convert into a gel once inside the duct, or amaterial that can fill the duct for accomplishing such purpose as havingthe duct easily identifiable for a medical procedure. See co-owned andco-pending applications U.S. Ser. No. 60/138,693 filed Jun. 11, 1999,herein incorporated by reference in its entirety.

A method of delivery of a substance to two or more ductal networks in abreast is provided. Access is established to two or more ductal networksin the breast through a ductal orifice of each ductal network.Thereafter a substance is delivered to and/or a fluid is collected fromtwo or more of the ductal networks. Establishing access can compriseinserting an access probe in each ductal orifice to be accessed. Atleast some of the access probes can be fluidly connected by a manifoldso that substance may be delivered simultaneously to the connectedprobes through the manifold. Thus, all of the access probes can befluidly connected to the manifold so that fluid may be deliveredsimultaneously to all probes. By the method, the substance can bedelivered simultaneously to all of the accessed ductal networks. Fluidcan be collected in separate receptacles for each ductal network. Accesscan be established to each of the ductal networks in a breast, so thatall the ducts on a breast are accessed and the agent is delivered to allof the ducts.

A method for delivering a fluid to two or more ductal networks in abreast comprises locating two or more ductal networks in a nipple of thebreast, inserting an access probe through an orifice of each of thelocated ductal networks: and infusing the fluid through a manifold toeach of the probes. The method can further comprise connectingindividual probes to the manifold so that the number of probes connectedto the manifold is the same as the number of probes inserted into ductalorifices. The method can further comprise providing an assembly of anumber of access probes greater than the number of ductal orifices. Theaccess probes can be attached to the manifold before or after accessingtheir respective ducts. The probes can be pre-loaded with a substanceand placed or attached to the manifold. Those access probes connected tothe manifold can be selectively blocked which are not inserted to aductal network. Thus, the system can provide for accessing as few or asmany of ductal networks desired, and for filling those ducts with asubstance, and/or retrieving from those ducts a fluid sample. The methodcan further comprise collecting fluid from each accessed ductal network,wherein the fluid is collected separately so that no one fluid from aductal network is mixed with fluid from another ductal network.

The invention also contemplates methods of accessing two or more breastducts for delivery of a substance. The substance can include e.g.therapeutic, diagnostic or prophylactic substances, or delivery of alavage fluid and conducting a lavage procedure of the breast ducts.Lavage procedures include delivering a substance for washing the duct(e.g. a lavage fluid) and retrieving or collecting that lavage fluid,albeit mixed with ductal fluid containing ductal cells and other ductalcontents. Lavage procedures can include delivery of the lavage fluidwith additives, or delivery of other agents before, after or duringdelivery of the lavage fluid.

The methods of accessing more than one breast duct occur using theapparatus of the invention such that all the ducts that the practitionerdesires to access are accessed and the substance delivered (and/orcollected in the case of a lavage procedure) at approximately the sametime, i.e. in the same procedure or simultaneously. Such simultaneousaccess results in the timesaving and efficiency benefits of theinvention. Delivery and subsequent fluid collection (where applicable tothe procedure) are achieved once all the ducts that the practitionerdesires to deliver a substance to have been accessed. Access occursusing a duct probe and/or lumen (e.g. a probe, catheter, cannula or thelike). After all the ducts are accessed, the delivery and/or collectioncan be implemented. With regard to the simultaneous nature of themethods it is understood that because the apparatus used in the methodsprovides a infusion inlet for the substance to be delivered, andprovides for access of more than one breast duct at the same time, thatthe delivery of the substance to the ducts occurs at the same time, orat about the same time. It is understood that during the deliveryprocedure adjustments can be made in order to ensure that the deliveryof a substance occurs in all the ducts about at the same time. Thus,e.g. e.g. a small duct may fill up faster than a larger duct, or where aparticular duct may require adjustments of the duct probe accessing itso that fluid flow can be maintained, but with for all practicalpurposes the delivery to all the ducts occurs at the same time, using asingle apparatus having at least more than one access lumen, deliveringa substance to all accessed ducts by a inlet.

As the methods of the invention require that the ducts to be accessedare accessed at about the same time, in the same procedure, thus, e.g.duct 1 is accessed by the duct probe, followed by duct 2, etc. until allthe ducts are accessed by a duct probe connected to an inflow lumen oran inflow lumen itself. The inflow lumens are connected to the inlet atthe outlets of the manifold. The lumens may be pre-primed or primedafter connection with the manifold. At that point simultaneous deliveryof the substance can occur by applying pressure to the syringe or otherdelivery instrument that contacts the inlet. The substance flows intothe inflow lumens through them to the accessed ducts. It is expected,anatomy of the human breast invariably dictating that not all ducts ofthe breast are exactly the same size or of the same capacity, that someducts may fill faster or slower than other ducts. With regulated andcontrolled and carefully monitored inflow pressure, however, thepractitioner can adjust, control and monitor the inflow of thesubstance, and observe each of the accessed ducts for whether deliveryof the substance is occurring and whether the collection from the duct(in the case of lavage) is optimal and sufficient.

The process of delivering a substance to more than one breast ductrequires connecting the apparatus described above (having an inletconnected at individual outlets to more than one probe lumen eachcapable of accessing a breast milk duct) to a breast. For example, wherethe breast has 7 ducts and the practitioner desires to access all ofthem, the apparatus for accessing those ducts will have 7 outlets toopen probe lumens capable of accessing those 7 ducts. Unused lumens thatare part of the apparatus can be capped or closed off. Once the lumenshave accessed the ducts, the substance can be delivered, e.g. by syringethrough the inlet of the manifold and out the outlets to the probelumens and to the ducts. Identification of the ductal orifices foraccessing them with a probe or other tool can be accomplished by avariety of means, including e.g. a characteristic electrical signal atthe nipple surface to indicate an orifice (see e.g. co-owned applicationattorney docket 00-042 filed Jan. 12, 2000) injecting or contacting thenipple with a dye or other substance that can be extruded from theorifices thereby identifying their location (see 08/931,786 filed Sep.16, 1997 and 09/153.564 filed Sep. 15, 1998), or other practical orsuitable means. Corresponding to these identification means, thepractitioner may also want to dekeratinize the nipple surface (includingmost importantly removing the keratin plugs from the ductal orifices) bymeans of applying a dekeratinizing agent (e.g. acetic acid, empigen, orcerumenex; the nipple can be dekeratinized with 5% -50% acetic acid toremove keratin and other potentially blocking and contaminatingsubstances from the ductal orifices) or by using a forceps to removevisually detectable plugs. Where it is desirable and important toidentify and access all the ducts on the nipple surface, e.g. where adiagnostic procedure (e.g. a lavage) is being conducted, a practitionerwill take care in being thorough with such identification and take careto access all identified ducts, and possibly take the time todouble-check with a parallel or complementary identification proceduresso that no ducts are missed.

As described for the apparatus embodiments, accessing the ducts can beaccomplished either by the inflow or infusion lumen (e.g. a catheter orcannula) directly, or the duct can first be accessed by a needle orprobe that dilates the duct and provides sufficient opening for thecatheter or other lumen to enter the duct. Where the orifice is accessedby a catheter having a modified tip being at least more rigid than thecatheter or lumen and having a graduated diameter for dilating the ductso that the substance flowing through the lumen can enter the duct, therigid tip can have a hook or an eye or some other such means to attach aline (to the skin of the breast) to keep the probe from sliding out ofthe duct. Where the duct probe is attached to the catheter, the probecan have a lumen so that the substance is delivered to the duct from thecatheter lumen into the probe lumen and into the duct. The attachedprobe can be graduated to dilate the duct so that the duct canaccommodate a lumen of sufficient diameter to efficiently deliver asubstance. Where a separate probe is used to access and dilate the ductin preparation for catheter access, the probe can be a solid member,having graduated diameter for dilating the duct. After the dilation iscomplete the dilator is removed and replaced with a catheter tip orother inflow lumen.

The methods of the invention include methods of ravaging more than onemilk duct at the same time by connecting a apparatus to the breast thathas an inlet connected to two or more outlets that each connect to aprobe or lumen capable of accessing a breast duct. The distal end of theprobe lumens can access a milk duct through a ductal orifice. Theapparatus may also include a collection receptacle off the probe lumento collect any fluid flowing out from or retrievable out from the duct.

An advantage of the methods of the invention providing simultaneousaccess of the breast ducts and retrieval of ductal fluid and cellularmaterial is that the added steps of massaging and squeezing need only bedone once for all the accessed ducts, thus limiting any patientdiscomfort or minimizing any potential tissue damage to the breasttissue, but requiring that a cycle of massaging and squeezing need onlybe conducted once per procedure per breast.

A kit for delivering a substance to a two or more of ductal networks ina breast is provided, having two or more of probes each having a lumenand being configured for introduction into a ductal network of thebreast, and instructions for use setting forth a method according tothose described and exemplified herein. A kit can comprise a manifoldhaving an inlet and at least twelve outlets, and at least twelve accessprobes connectable to the outlets on the manifold, wherein the accessprobes are configured for insertion through an orifice of a ductalnetwork of a breast. The kit can further comprise a separate collectionreceptacle for each probe.

Kits for use by a practitioner or patient can comprise the apparatusdescribed herein, along with instructions for use of the apparatus. Thekits can further comprise attachable or attached inflow lumens (e.g.catheters), duct probes (e.g. a graduated duct probe), and/or catheterswith connected duct probes at their distal ends. The catheter may havethe graduated duct probe attached to it at the distal end for accessingthe duct. The graduated duct probe can have an anchoring member such asdescribe herein for attaching the probe (or other access member) and itsattached catheter into the duct and preventing it from sliding out.Where the probe is unattached to the catheter, and is used for dilatingthe orifice, the catheter will have a tip appropriate for accessing thedilated duct upon removal of the probe (or probes). The kit can alsoinclude appropriate reagents e.g. wash agents, dekeratinizing agents,and ductal orifice identifying agents. The kit may also contain thesubstance for delivery, e.g. a wash fluid for performing a lavage, or adiagnostic agent, prophylactic or therapeutic agent for delivery, or anagent for occupying space in the duct.

The kit may also contain fluid additives or other agents to beadministered to the duct in order to facilitate some part of theprocedure. The kit can also have vessels, e.g. collection tubes forcollecting lavage and ductal fluid from an outflow lumen. Thesecollection tubes can contain substances that anticipate analysis of thecollection fluid, including, e.g. preservative in the tubes. Any kitwill contain complete directions for use of the items supplied in thekit for performing the delivery or lavage procedure desired by the kituser.

The following table illustrates results obtainable from a lavageprocedure of the right and left breast of a patient undergoing adiagnostic lavage procedure to identify whether a cancer or pre-cancercondition exists in any of the ducts of the patient. Single lavageprocedures are conducted for the right breast having 7 ducts and theleft breast having 9 ducts TABLE 1 Diagnosis Breast/Duct Lavage FluidDelivered Fluid Collected Cells Collected (cytology) R-1 PBS - 20 ml++++++ ++++ scattered clusters of benign unremarkable ductal cells R-2PBS - 20 ml +++++++ +++++ ADH: some ductal cells exhibiting cytologicalcharacteristics of atypical ductal hyperplasia R-3 PBS - 20 ml ++++ ++scattered clusters of benign unremarkable ductai cells R-4 PBS - 20 ml+++++ +++ scattered clusters of benign unremarkable ductal cells R-5PBS - 20 ml +++ + Hyperplasia: some ductal cells exhibiting cytologicalcharacteristics of ductal hyperplasia without atypia R-6 PBS - 20 ml+++++++ +++++ ADH: some ductal cells exhibiting cytologicalcharacteristics of atypical ductal hyperplasia R-7 PBS - 20 ml +++++++++ scattered clusters of benign unremarkable ductal cells L-1 PBS - 20ml ++++ + scattered clusters of benign unremarkable ductal cells L-2PBS - 20 ml +++++ ++ scattered clusters of benign unremarkable ductalcells L-3 PBS - 20 ml +++++ ++++ ADH: some ductal cells exhibitingcytological characteristics of atypical ductal hyperplasia L-4 PBS - 20ml ++++++ ++++ ADH: some ductal cells exhibiting cytologicalcharacteristics of atypical ductal hyperplasia L-5 PBS - 20 ml ++++++++++++ ADH: some ductal cells exhibiting cytological characteristics ofatypical ductal hyperplasia L-6 PBS - 20 ml ++++ ++ scattered clustersof benign unremarkable ductal cells L-7 PBS - 20 ml +++ + scatteredclusters of benign unremarkable ductal cells L-8 PBS - 20 ml +++++ +++Hyperplasia: some ductal cells exhibiting cytological characteristics ofductal hyperplasia without atypia L-9 PBS - 20 ml ++++ ++ Hyperplasia:some ductal cells exhibiting cytological characteristics of ductalhyperplasia without atypia

Table 2 represents a hypothetical treatment protocol of the hypotheticalpatient tested in Table 1 During each drug administration, the rightbreast ducts are accessed at the same time (R-2 and R-6) and the leftbreast ducts are accessed in a separated procedure also at the same time(L-3, L-4, L-5). TABLE 2 Repeat Breast/ Frequency of diagnosis by DuctDrug Dosage Administration lavage R-2 tamoxifen 10 mg/in time one weeklyevery 3 months releasing gel R-6 tamoxifen 10 mg/in time one weeklyevery 3 months releasing gel L-3 tamoxifen 10 mg/in time one weeklyevery 3 months releasing gel L-4 tamoxifen 10 mg/in time one weeklyevery 3 months releasing gel L-5 tamoxifen 10 mg/in time one weeklyevery 3 months releasing gel

EXAMPLES

1. Cell Collection of Milk Duct Lavage of a Human Patient

The ducts of the right breast of a patient are identified by acharacteristic electrical signal and as the nipple surface is probedwith an electrode, areas of low electrical impedance (see co-owned andco-pending application attorney docket 00-042 filed Jan. 12, 2000 fordetails) are accessed with a duct probe attached to a dual lumencatheter. The electrode may be a probe capable also of accessing anddilating a duct that indicates a spot of low impedance. As such once theidentification, access and dilation by the probe are accomplished theprobe can be replaced by an appropriate lumen. e.g. a dual lumencatheter. Areas of high impedance are dekeratinized by application ofacetic acid mixed with Velvacrol (50% v/w), a pharmaceutical vehiclecomprising an aqueous mixture of petrolatum/mineral oil, acetyl alcohol,sodium laurel sulfate, cholesterol, methylparaben, butylparaben, andpropylparaben. To keep the acetic acid in solution, methyl cellulose(100 mg) is pre-added to the Velvacrol (5 g). The mixture possesses auniform pasty consistence and is applied to the nipple as an ointment orpaste. The keratinolytic agent is typically left on the nipple for 24hours or longer to remove the keratin plugs from the ductal orifices.The identified orifices are then accessed with a duct probe. Once a ducthas been accessed, the probe is anchored into the duct by attaching aline to the probe at an eye (or loop) on the probe. The line is thenaffixed to the breast skin with an adhesive bandage that holds a linethat is connected to the probe. The loop rests at about the nipplesurface. Once all the ducts are accessed the area of the nipple surfacethoroughly re-probed with the electrode to determine that all the ductson that breast have been identified and that none have been missed. Thepatient has 10 ducts on the right breast. Collection tubes connected tothe 10 outflow lumens have preservative in them.

A lavage fluid of 200 ml normal saline is inserted into a syringe thatconnects to the inlet of the connected apparatus. The syringe capacityis 250 ml. The plunger of the syringe is pushed to the 150 mark at asteady rate and the status of the duct probes, dual lumens and ductalorifices is carefully observed. Fluid is collected in separatecollection tubes connected to the lumens. The breast is then massagedand squeezed gently from the base to the areola. The syringe at theinlet is pushed to 100 ml and the breast is squeezed and massaged at thesame time. This second fraction is collected in new collection tubes andlabeled accordingly. The breast is squeezed and massaged again. Another50 ml is pushed out from the syringe, meanwhile the breast is squeezedand massaged and a third fraction collected. A fourth aliquot of 50 mlis delivered, and the breast also squeezed and massaged as the fourthfraction is collected.

A portion of fluid from each of the 4 fractions from each of the 10ducts is transferred to a new tube and the cells spun down. Theresulting cells are analyzed by cytology.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Although the foregoing invention has beendescribed in some detail by way of illustration and example for purposesof clarity of understanding, it will be readily apparent to those ofordinary skill in the art in light of the teachings of this inventionthat certain changes and modifications may be made thereto withoutdeparting from the spirit or scope of the appended claims.

1-37. (canceled)
 38. An apparatus for simultaneously accessing two ormore ductal networks in a breast, said apparatus comprising: a manifoldhaving an inlet for receiving fluid and at least two outlets; at leasttwo individual access probes, each probe having a lumen connected to arespective one of said at least two outlets and configured for insertionthrough an orifice of a ductal network; a means for anchoring saidaccess probes into said ductal network; and a collection tube connectedto at least one probe for receiving biological material from within thebreast.
 39. An apparatus as in claim 38, wherein the manifold has atleast three outlets connectable to at least three respective probes. 40.An apparatus as in claim 38, wherein the manifold has at least twelveoutlets connectable to at least 12 respective probes.
 41. An apparatusas in claim 38, wherein the probes are removably connectable to themanifold.
 42. An apparatus as in claim 38, wherein at least one probecomprises a fluid control device capable of controlling fluid flow inthe lumen of said at least one probe.
 43. An apparatus as in claim 38,wherein a number of the probes are each connected to a respective one ofthe outlets, and said number is equal to the number of the ductalnetworks to be accessed.
 44. An apparatus as in claim 43, wherein atleast one of said outlets is unconnected to a respective one of saidprobes, and the at least one unconnected outlet is closed to fluid flow.45. An apparatus as in claim 43 wherein the collection tube furthercomprises a fluid control device capable of controlling fluid flow inthe collection tube.
 46. An apparatus as in claim 43 wherein at leastone of said probes further comprises a fluid control device capable ofcontrolling fluid flow in said lumen of said at least one probe.
 47. Anapparatus as in claim 43 further comprising a plurality of collectiontubes, wherein each collection tube is connected to a respective one ofsaid probes.
 48. An apparatus as in claim 47 wherein each probecomprises a fluid control device capable of controlling fluid flow inthe lumen of said probe, and each collection tube comprises a fluidcontrol device capable of controlling fluid flow in said collectiontube.
 49. An apparatus as in claim 47 wherein at least one of saidoutlets is unconnected to a respective one of said probes and the atleast one unconnected outlet is closed to fluid flow.
 50. An apparatusas in claim 40, wherein the probes are removably connectable to themanifold and wherein at least one of said outlets is configured, uponremoval of a probe therefrom, for closure to fluid flow.
 51. Anapparatus as in claim 38 wherein the collection tube further comprises afluid control device capable of controlling fluid flow in saidcollection tube, and wherein at least one of said probes furthercomprises a fluid control device capable of controlling fluid flow inthe lumen of said at least one of said probes.
 52. An apparatus as inclaim 38 further comprising at least two collection tubes, eachconnected to a respective one of the at least two probes, for receivingbiological material from within the breast.
 53. An apparatus as in claim38 wherein each probe comprises a fluid control device capable ofcontrolling fluid flow in the respective lumen of the probe.
 54. Anapparatus as in claim 38 wherein each probe comprises a fluid controldevice capable of controlling fluid flow in the lumen of said probe, andthe collection tube comprises a fluid control device capable ofcontrolling fluid flow in said collection tube.
 55. An apparatus as inclaim 38, further comprising a first device connectable to the manifoldfor infusing fluid within the breast.
 56. An apparatus as in claim 55,wherein the manifold has at least three outlets connectable to at leastthree respective probes.
 57. An apparatus as in claim 55, wherein themanifold has at least 12 outlets connectable to at least 12 respectiveprobes.
 58. An apparatus as in claim 55 wherein the collection tubefurther comprises a fluid control device capable of controlling fluidflow in the collection tube.
 59. An apparatus as in claim 55, whereinthe number of outlets exceeds the number of probes and at least one ofthe outlets is unconnected to a probe and closed to fluid flow.
 60. Anapparatus as in claim 55 wherein said first device is capable ofcontaining a wash agent.
 61. An apparatus as in claim 55 wherein saidfirst device is capable of containing a diagnostic agent.
 62. Anapparatus as in claim 55 wherein said first device capable of containingan agent for occupying space in a duct.
 63. An apparatus as in claim 55,wherein the first device is a syringe.
 64. An apparatus as in claim 55,further comprising a second device connectable to the collection tubefor collecting biological material from within the breast.
 65. Anapparatus as in claim 64 further comprising a plurality of collectiontubes, each connected to a respective one of said probes, and whereineach collection tube comprises a second device connectable to saidcollection tube for collecting biological material from within thebreast.
 66. An apparatus as in claim 64, wherein the second device is asyringe.
 67. An apparatus as in claim 38, wherein said manifold iscapable of containing a wash agent.
 68. An apparatus as in claim 38,wherein said manifold is capable of containing a diagnostic agent. 69.An apparatus as in claim 38, wherein said manifold is capable ofcontaining an agent for occupying space in a duct.